Aims Sumatriptan is a 5-HT 1B/1D -receptor agonist which also has affinity for 5-HT 1F -receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT 1B -receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT 1F -receptors has also been identified and this study addresses the possibility of whether 5-HT 1F -receptor activation contributes to vasoconstriction. Methods The ability of two selective 5-HT 1B/1D -receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT 1F -receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT 1B/1D -receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HT 1F -receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT 1B -, 5-HT 1D -and 5-HT 1F -receptors expressed in CHO cell lines. Results GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA 2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT 1B -receptor affinity (r=0.93, P=0.002) but not with 5-HT 1D -or 5-HT 1F -receptor affinity (r=0. 74, P=0.06; r=0.31, P=0.49, respectively). Conclusions These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT 1B -receptor mediated with little if any contribution from 5-HT 1F -receptor activation.

3 (+)-PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC50 values of 33 nM (pEC5o= 7.48+0.10, n = 10) and 38 nM (pEC50= 7.42+0.15, n = 5), respectively. No effects of (+)-PD 128907 (100 nM) were observed on glutamate or GABA-mediated synaptic potentials elicited by focal bipolar stimulation. 4 L-741,626 antagonized these effects of (+ )-PD 128907 in a concentration-dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (pKB= 7.71 + 0.14)in the ventral tegmental area and 11 nM (pKB = 7.95 + 0.18) in the substantia nigra pars compacta.5 (+)-PD128907 also inhibited dopamine release in the caudate-putamen with an ECso of 66 nM (n = 5). The affinity of L-741,626 for these nerve terminal autoreceptors (pKB= 7.71 + 0.06; = 20 nM) was identical to that observed on midbrain dopamine neurones. 6 These data demonstrate that the D3 receptor ligand (+)-PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D2 receptor antagonist L-741,626 for receptors activated by (+ )-PD 128907, was more consistent with an action on D2 autoreceptors rather than upon a D3 dopamine receptor subtype.

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